Title:Design and Molecular Docking Studies of N-Mannich Base Derivatives of
Primaquine Bearing Isatin on the Targets involved in the Pathophysiology
of Cerebral Malaria
Volume: 22
Issue: 6
Author(s): Deepika Purohit, Rohit Dutt, Pawan Kumar, Sahil Kumar*Ajit Kumar*
Affiliation:
- Department of Pharmaceutical
Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and
Research University, New Delhi, 110017, India
- Centre For Bioinformatics, Maharshi Dayanand University, Rohtak 124001, India
Keywords:
Cerebral malaria, cystein protease falcipain, dipeptidyl aminopeptidase, glycogen synthase kinase, molecular docking, pharmacokinetics.
Abstract:
Background: Malaria is considered one of the life-threatening mosquito-borne infectious
diseases responsible for approximately more than 4,00,000 deaths every year all over the world. Plasmodium
falciparum and Plasmodium vivax are widespread species, but infections caused by the former
are of great concern.
Objective: Among the various forms of infections associated with Plasmodium falciparum, cerebral
malaria (CM) is the most severe neurological complication, accounting for almost 13% of all malariarelated
mortality. The development of effective therapeutics is urgently needed to overcome the fatality
of this dreadful disease.
Methods: The present work attempted to design and virtually screen a chemical library of 75 molecules
(N-Mannich base derivatives of primaquine bearing isatin moiety as heterocyclic) by molecular
docking studies against anti-malarial target proteins-Cystein Protease Falcipain-2; Dipeptidyl Aminopeptidase-
1; Dipeptidyl Aminopeptidase-3 and Glycogen synthase Kinase-3β receptors, for evaluating
their anti-malarial potential. Among all studied anti-malarial target receptors, the designed molecules
showed an overall higher affinity for Dipeptidyl Aminopeptidase-3. Furthermore, the molecules
were analyzed for binding affinity and drug-like properties using Lipinski rules, and 30 best hits were
shortlisted and analyzed for the pharmacokinetic profile.
Results: Two of these hits were found to be more toxic than primaquine, hence were omitted in further
analysis. Later, these 28 hits were docked against two target proteins, (a) Plasmodium falciparum
erythrocyte membrane protein-1 and (b) Intracellular adhesion molecule-1, to determine their efficiency
against cerebral malaria, and the results were recorded. Analysis of docking results led to the identification
of the 8 studied molecules as lead molecules which were selected for chemical synthesis,
in vivo studies, and further preclinical evaluation.
Conclusion: The molecule DSR 11 was predicted as the most appropriate lead molecule for anti-CM
activity in the present investigation apart from the other seven molecules (DSR4, DSR26, DSR38,
DSR40, DSR49, DSR56, and DSR70).
